“Mitochondria myopathies are genetic diseases due to mutations in the mitochondrial or nuclear DNA and characterized by defective oxidative phosphorylation. No cure is currently available for these conditions. AAV-based gene therapy is a highly promising tool for the etiological treatment of congenital myopathies.
We tested a recently developed, liver-detargeted, myotropic AAV vector in a muscle-specific knockout mouse for Cox15 (Cox15sm), lacking an enzyme involved in the biosynthesis of heme A, the prosthetic group of cytochrome c oxidase (COX). The Cox15sm mouse is characterized by severely reduced motor performance, myopathy, and COX deficiency.
AAV-Cox15 vector was injected in one-month-old Cox15sm mice at 10^12 and 5×10^12 vg/Kg and their motor performance was monitored over 8 weeks. Both cohorts had reduced running capacity at the beginning of the treatment, and started to improve four and two weeks from the AAV injection, respectively, with the motor performance increasing almost 10 times, i.e. from 50 to 500 meters. No increase in motor performance was observed in untreated Cox15sm littermates. Notably, the widely used AAV9 serotype was far less effective in increasing the motor performance in Cox15sm mice at the same titers.
Post-mortem analysis of skeletal muscle revealed marked amelioration of the myopathy and partially increased COX activity.
Thus, we have identified a highly effective myotropic AAV, which can be used in mitochondrial and other congenital myopathies at much lower titers than currently available serotypes.”